The long-term goal is to exploit a naturally occurring bladder disease in domestic cats (Feline Interstitial Cystitis - FIC) to gain a better understanding of a painful bladder disorder in humans called interstitial cystitis (IC), and by extension other pelvic pain syndromes. This is because many patients with IC also have IBS and other neurovisceral disorders that predominantly affect women, and appear to be exacerbated by stress. The studies proposed here are designed to further investigate the causes of these neurological alterations in controlled studies of cats diagnosed with IC and healthy cats. The studies are needed to elucidate the significance of the underlying neurological abnormalities present in human patients with IC. They also are intended to guide the choice of subsequent studies toward the primary systems involved in IC, with the eventual goal of identifying rational treatments of IC in human beings. The overall objective of this proposal is to test the hypothesis that interactions between CRF, sex hormones and the alpha-2 adrenoceptor (alpha2-AR) play a role in the sex difference in stress-responsiveness of cats with FIC. The rationale for the proposal is based on 1) clinical evidence that females are more prone to develop IC than males (intact males in cats), 2) the gap in knowledge in factors that may account for such sex differences due to the paucity of experimental data in this field, 3) evidence from our recent studies pointing to a role of alpha2-AR dysfunction in cats with IC, and 4) existing evidence that urothelial and alpha2-AR function can be modulated by testosterone, estrogen, and oxytocin. By studying a natural occurring animal model of IC which shares many features with a rat model of IBS, and with the respective human patient populations, we will be able to assess the role of sex hormones on the expression of these diseases.